Promoter-controlled infectivity-enhanced conditionally replicative adenoviral vectors for the treatment of gastric cancer
Promoter-controlled infectivity-enhanced conditionally replicative adenoviral vectors for the treatment of gastric cancer
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DOI：
10.1007/s00535-004-1490-y
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发表时间：
2005-01-01
影响因子：
6.3
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
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作者：
Ono, HA;Davydova, JG;Yamamoto, M
背景胃癌是全球第四大常见恶性肿瘤。腺病毒载体因其高转导效率而被广泛应用于多种肿瘤的基因治疗。然而，由于柯萨奇-腺病毒受体（CAR）的有限表达，胃肠道癌细胞的感染性差。此外，很少有肿瘤特异性启动子（TSP）的特点是这种类型的癌症。为了克服这些问题，我们提出了TSP驱动的条件复制腺病毒（CRAds）与纤维修饰的病毒治疗胃癌。方法.我们评估了八种TSP在胃癌细胞系中的表达谱，并在CRAd杀细胞作用的背景下评估了有希望的候选物。接下来，在胃癌细胞系中分析了通过纤维修饰的感染性增强。最后，我们将TSP驱动的CRAD与纤维改性相结合，以增强杀伤效果。结果在8种TSP中，中期因子（MK）和环氧合酶-2（考克斯-2 M和考克斯-2L）启动子在胃癌细胞中表现出高转录活性。当这些启动子用于CRAd环境中时，考克斯-2 CRAd引起最强的杀细胞作用。用展示5/3嵌合纤维的腺病毒载体观察到最大的感染性增强。同样，具有5/3嵌合纤维的考克斯-2 CRAd在胃癌细胞系中显示出最强的细胞杀伤作用。因此，具有5/3嵌合纤维修饰的考克斯-2 CRAds在胃癌细胞中显示出良好的选择性和感染性，以产生增强的溶瘤作用。结论. 5/3嵌合纤维修饰的考克斯-2 CRAds有望用于胃癌的病毒治疗。
Background. Gastric cancer is the fourth most common malignancy worldwide. Adenoviral vectors (Ads) have been applied for gene therapy of various cancers because of their high transduction efficiency. However, the infectivity of gastrointestinal cancer cells is poor due to the limited expression of the Coxsackie-adenovirus receptor (CAR). In addition, few tumor-specific promoters (TSPs) have been characterized for this type of cancer. To overcome these problems, we proposed TSP-driven conditionally replicating adenoviruses (CRAds) with fiber modification for virotherapy of gastric cancer. Methods. We assessed the expression profile of eight TSPs in gastric cancer cell lines and evaluated promising candidates in the context of CRAd cytocidal effect. Next, infectivity enhancement by fiber modifications was analyzed in the gastric cancer cell lines. Finally, we combined the TSP-driven CRAds of choice with the fiber modifications to augment the killing effect. Results. Out of the eight TSPs, the midkine (MK) and cyclooxygenase-2 (Cox-2M and Cox-2L) promoters showed high transcriptional activity in gastric cancer cells. When these promoters were used in a CRAd context, Cox-2 CRAds elicited the strongest cytocidal effect. The greatest infectivity enhancement was observed with adenoviral vectors displaying 5/3 chimeric fibers. Likewise, Cox-2 CRAds with 5/3 chimeric fibers showed the strongest cytocidal effect in gastric cancer cell lines. Therefore, Cox-2 CRAds with 5/3 chimeric fiber modification showed good selectivity and infectivity in gastric cancer cells to yield enhanced oncolysis. Conclusions. Cox-2 CRAds with 5/3 chimeric fiber modification are promising for virotherapy of gastric cancer.